Diabetes is a major international health problem, affecting 100 million people worldwide. In the U.S. alone, 10 million people suffer the effects of diabetes; it is estimated that an additional 5 million people have diabetes, but have not yet been diagnosed. The physical complications that can result from the abnormally high blood glucose levels associated with diabetes are severe. In the U.S., it is the leading cause of end-stage renal failure, lower limb amputation, and blindness in adults over the age of 20. The incidence of heart disease, stroke, and high blood pressure in the diabetic population is more than double that of the non-diabetic population. As a consequence, diabetes is the seventh leading cause of death in the U.S. (Centers for Disease Control and Prevention, National Diabetes Fact Sheet).
Based on pathology and etiology, diabetes is separated into several distinct categories. Type I diabetes, which affects 5-10% of diabetic patients, is characterized by a complete inability of the individual's pancreas to produce insulin as a result of the destruction of pancreatic--islet cells by immune cells. Thus, Type I diabetes is successfully treated only by supplementation with insulin. Type II diabetes, the form that affects .about.90% of diabetics, is characterized by resistance to the effects of insulin and an eventual decline in compensatory insulin production. Type II diabetes can be successfully treated with insulin; however insulin therapy in NIDDM often results in weight gain and hypoglycemia. The most common alternatives to insulin therapy for the treatment of Type II diabetes utilize agents that enhance insulin production by pancreatic--islet cells and/or enhance cellular response to insulin (reviewed in Turner, DDT 1:109 (1996); Hoist, DDT 2:128 (1997)). The currently available therapies have substantial side effects that can limit their usefulness.
Type II diabetic individuals generally exhibit poor control over blood glucose levels, which is manifested as persistent and sustained elevation in glucose levels following food consumption as well as by unusually high blood glucose levels during fasting periods. The acute hyperglycemia experienced after eating is due to diminished glucose uptake from the blood by bodily tissues such as adipose and skeletal muscle, most likely the result of resistance to the normal effects of insulin on these tissues. The relative hyperglycemia experienced by the Type II diabetic patient during periods of fasting is believed to be due to increased glucose production (gluconeogenesis) by cells in the liver (Magnusson, et. al., J. Clin. Invest. 90:1323 (1992)), which may also result from decreased hepatic responsiveness to insulin (Sanchez-Gutierrez, Endocrinology 134:1868 (1994)). Current therapies are directed at decreasing hyperglycemia by increasing uptake of circulating glucose from the blood. However, they do not effectively alleviate the hyperglycemia experienced during fasting periods which results from elevated hepatic gluconeogenesis.
Gluconeogenesis is regulated physiologically at several metabolic points, with the key rate-limiting step being the conversion of fructose-1,6-bisphosphate to fructose-6-phosphate. This step is controlled by the activity of fructose-1,6-bisphosphatase (FBPase), an enzyme which is unique to the gluconeogenesis pathway (reviewed in Hers, J. Inher. Metab. Dis. 13:395 (1990); Benkovic and deMaine, Adv. Enzymol 53:45 (1982)). In vivo, FBPase activity is controlled by the cellular levels of its inhibitors, adenosine monophosphate (AMP) and fructose-2,6-bisphosphate (F-2,6-P.sub.2 ; Hers, supra). FBPase activity has been regulated experimentally in vitro and in isolated liver hepatocytes by the use of a naturally occurring analog of AMP, AICA ribose (Vincent, et. al., Pur. Pyrim. Metab. in Man 8:359 (1991). Inhibitors of FBPase could logically be predicted to cause decreased blood glucose levels through the inhibition of gluconeogenesis. Because of its unique and critical role in gluconeogenesis, FBPase forms an attractive target for therapeutic intervention for the treatment of hyperglycemia in diabetes or in other diseases where hyperglycemia is manifested.